SI9300584A - Therapeutic agents for treatment of obesity and affective disorders and processes for their preparation - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof in which m is an integer from 1 to 3; n is an integer from 2 to 6; R1 is phenyl optionally substituted by one or more substituents selected from halo, hydroxy, alkoxy, alkanoyl, alkyl, halogenated alkyl, alkylthio, alkylsulphinyl, alkylsulphonyl, cyano, nitro, optionally substituted amino, optionally substituted sulphamoyl, optionally substituted carbamoyl or phenyl, or R1 is naphthyl; R2 is H, alkyl or phenyl; R3 is H, alkyl, alkenyl or alkoxyalkyl; R4 is H or hydroxy; and R5 is H or together with R4 represents a bond; have utility in the treatment of obesity and affective disorders such as depression and anxiety.

Description

and pharmaceutically acceptable salts thereof, in which m is an integer from 1 to 3; n is an integer from 2 to 6; R1 is phenyl optionally substituted by one or more substituents selected from: halo, hydroxy, alkoxy, alkanoyl, alkyl, halogenated alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, nitro, optionally substituted amino group, optionally substituted carbamoyl, optionally substituted carbamoyl; or phenyl or R1 is naphthyl; R 2 is H, alkyl or phenyl; R3 is H, alkyl, alkenyl, or alkoxyalkyl; R4 is H or hydroxy; and R 5 is H or together with R 4 represents a bond; which are useful in the treatment of obesity and emotional disorders such as depression and anxiety.

THERAPEUTIC SUBSTANCES FOR TREATMENT OF OBESITY AND EMOTIONAL DISORDERS AND PROCEDURES FOR THEIR PREPARATION

The present invention relates to novel therapeutic agents, methods for their preparation, pharmaceutical compositions containing them, and their use in the treatment of obesity and emotional disorders such as depression and anxiety.

The present invention provides compounds of formula I \

and pharmaceutically acceptable salts thereof, in which m is an integer from 1 to 3;

n is an integer from 2 to 6;

R1 is phenyl optionally substituted by one or more substituents selected from: halo, hydroxy, alkoxy containing 1 to 3 carbon atoms, alkanoyl containing 2 or 3 carbon atoms, alkyl containing 1 to 3 carbon atoms, halogenated alkyl containing 1 to 3 carbon atoms, alkylthio containing 1 to 3 carbon atoms, alkylsulfinyl containing 1 to 3 carbon atoms, alkylsulfonyl containing 1 to 3 carbon atoms, cyano, nitro, amino optionally substituted by 1 or 2 alkyl groups each containing 1 to 3 carbon atoms, carbamoyl optionally substituted with 1 to 2 alkyl groups each containing 1 to 3 carbon atoms, or phenyl, or R1 is naphthyl;

R 2 is H, alkyl containing 1 to 3 carbon atoms, or phenyl;

R ₃ is H, alkyl containing 1 to 6 carbon atoms, alkenyl containing 3 to 6 carbon atoms or alkoxyalkyl in which the alkoxy group contains 1 to 4 carbon atoms and the alkyl group 2 to 4 carbon atoms;

R ₄ is H or hydroxy; and

Rg is H or together with R ₄ represents a bond.

In preferred compounds of formula I, n is 4 or 5.

In preferred compounds of formula I, m is 1 or 2.

In preferred compounds of formula I, R1 is phenyl optionally substituted by one or more substituents selected from: halo (for example fluoro, chloro, bromo or iodo), hydroxy, halogenated alkyl containing 1 to 3 carbon atoms in which halo fluoro, alkoxy containing 1 to 2 carbon atoms, or phenyl, or R1 is naphthyl. In more preferred compounds of formula I, R 1 is phenyl optionally substituted by one or more substituents selected from: chloro, fluoro, hydroxy, trifluoromethyl, methoxy or phenyl, or R 1 is naphthyl. In particularly preferred compounds of formula I, R1 is phenyl, 3-chlorophenyl, 4-chlorophenyl,

3,4-dichlorophenyl, 4-fluorophenyl, 3- (trifluoromethyl) phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-biphenyl or 2-naphthyl.

In preferred compounds of formula I, R 8 is H.

In preferred compounds of the formula IR ₃ means H, alkyl containing 1 to 3 carbon atoms, alkenyl containing 3 to 6 carbon atoms, or alkoxyalkyl in which the alkoxy group contains 1 to 3 carbon atoms and alkyl having 2 or 3 carbon atoms atoms. In more preferred compounds of the formula IR ₃ is H, methyl, ethyl, propyl, allyl or 2methoxyethyl. In particularly preferred compounds of formula IR ₃ is H.

In preferred compounds of formula I, R ₄ is hydroxy and R is H, R4 and Rg are both H, or R4 and Rg together represent a bond. In more preferred compounds of formula I, R4 and Rg together represent a bond.

The compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. (+) - tartrate, (-) - tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. The compounds of formula I and their salts may exist in the form of salts (for example hydrates).

Certain compounds of formula I may exist in more than one crystalline form and the present invention includes each crystalline form and mixtures thereof.

Compounds of formula I containing one or more non-h centers exist in various optically active forms. When the compounds of formula I contain a single center, these compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. Enantiomers can be separated by methods known to those skilled in the art, for example by forming diastereoisomeric salts, which can be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomerspecific reagent, for example by enzymatic esterification; or gas or liquid chromatography in a chiral environment, for example on a chiral carrier, for example silica gel with bound chiral ligand, or in the presence of a chiral solvent. It will be appreciated that where the active group is transformed by the separation procedures described above, the next step is required to convert the product to the active group. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis, using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.

Specific compounds of formula I are;

r

5- (4-chlorophenyl) -1-azaspiro [5.5.5] hendec-4-ene;

Γ Ί

5- (3-chlorophenyl) -1-azaspiro [5.5Jundek-4-ene;

5- (3,4-dichlorophenyl) -1-azaspiro [5.5] undec-4-ene;

r '' '

5- (4-fluorophenyl) -1-azaspiro [5.5jundec-4-ene;

5- [3- (Trifluoromethyl) phenyl-1-azaspiro [5.5jundec-4-ene;

5- (2-naphthyl) -1-azaspiro [5.5jundec-4-ene;

5- (4-hydroxyphenyl) -1-azaspiro [5.5-iundec-4-ene;

Γ i

5- (4-chlorophenyl) -1-methyl-1-azaspiro 5.5jundec-4-ene;

10- (4-chlorophenyl) -6-azaspiro [4.5Jdec-9-ene;

5- (4-chlorophenyl) -5-hydroxy-1-azaspiro [5.5: undecane;

5- (4-chlorophenyl) -1-ethyl-5-hydroxy-1-azaspiro [beta]. 5 j undecane;

5- (3-chlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane;

5- (3,4-Dichlorophenyl) -5-hydroxy-1-azaspiro [5.5judecane;

5- (4-chlorophenyl) -1-azaspiro [δ.δ] undecane;

5- (4-methoxyphenyl) -1-azaspiro [5.5lundecane;

5- (4-chlorophenyl) -1-propyl-1-azaspiro [δ.5] undec-4-ene;

r T

1- al 1-5- (4-chlorophenyl) -1-azaspiro [5.5jundec-4-ene;

5- (4-chlorophenyl) -1- (2-methoxyethyl) -1-azaspiro [5.5] undec-4-ene; 5-phenyl-1-azaspiro {5.5jundec-4-ene;

5- (4-bi-phenyl) -1-azaspiro [5.5] undec-4-ene;

4- (4-chlorophenyl) -1-azaspiro [4.5] undec-3-ene;

and pharmaceutically acceptable salts thereof.

The present invention also includes pharmaceutical compositions containing therapeutically effective amounts of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

The term active compound as used herein refers to a compound of formula I. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Therefore, the therapeutic compositions of this invention may be in the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the pharmaceutical art. The compositions of the invention may contain 0.1-99% by weight of the active compound. The compositions of the invention are usually prepared in the form of a dosage unit. The preferred dosage unit of the active ingredient is 1 to 500 mg. The excipients used in the preparation of these compositions are excipients known in the pharmaceutical art.

Oral administration compositions are preferred compositions of the invention and are known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are excipients known in the pharmaceutical art. The tablets may be prepared by mixing the active compound with an inert diluent, such as calcium phosphate, in the presence of disintegrating agents such as corn starch and lubricants, such as magnesium stearate, and tabletting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art to obtain the sustained release of the compounds of this invention. Such tablets may, if desired, be provided with enteric coatings, for example by the use of cellulose acetate phthalate, by articulated procedures. Similarly, capsules, for example, hard or soft gelatin capsules containing the active compound with or without added excipients, can be prepared in conventional ways and, if desired, coated with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carbosquimethylcellulose and oily suspensions containing a compound of the present invention in a suitable vegetable oil, such as peanut oil .

The active compound can be formulated into granules with or without additional excipients. The pellets can be swallowed directly by the patient, or added to a suitable liquid carrier (such as water) before swallowing. Granules may contain disintegrating agents (for example, a pharmaceutically acceptable effervescent vapor formed by an acid and a carbonate or bicarbonate salt) to facilitate dispersion in an aqueous medium.

The compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with a base of coconut butter or polyethylene glycol.

The compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.

Topical compositions may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed such that the compounds are in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing a pharmaceutically active compound with a local carrier such as mineral oil, petroleum ether and / or wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerator such as dimethyl sulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable base in the form of a cream or ointment. The amount of active compound contained in the topical formulation should be such that the therapeutically effective amount of the compound is released over the period of time the intended topical formulation is intended to be present on the skin.

The compounds of the present invention may also be administered by continuous infusion, either from an external source, for example by intravenous infusion, or from a source of a compound present in the body. Internal sources include implanted reservoirs containing a sustained-release infusion compound, for example by osmosis, and implants, which may be (a) a liquid, such as a suspension or solution in a pharmaceutically acceptable oil of the infusion compound, for example in the form of a derivative very moderately soluble in water, such as dodecanoate salt or ester, or (b) a solid in the form of an implanted carrier (for example, synthetic resin or waxy material) for the compound to be administered by infusion. The carrier may be a single body containing the entire compound, or a series of multiple bodies, each containing a portion of the compound to be released. The amount of active compound present in the internal source must be such that the therapeutically effective amount of the compound is released over a long period of time.

In some formulations, it may be advantageous to use the compounds of the present invention in the form of particles of very small size, for example, such as those obtained by grinding with fluid energy.

In the compositions of the present invention, the active compound may, if desired, be combined with other pharmacologically active ingredients.

Pharmaceutical compositions containing therapeutically effective amounts of a compound of Formula I can be used to treat obesity and emotional disorders such as depression and anxiety. Although the precise amount of the active compound given in such treatment will depend on many factors, such as the patient's age, severity, and past course of the disease, and is a matter of thorough medical judgment, the amount of active compound administered per day in in the range of 1 to 1000 mg, preferably 5 to 500 mg, given as one or more doses, once or several times during the day.

In another aspect, the invention provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of obesity and emotional disorders such as depression and anxiety.

We will now describe processes for the preparation of compounds of formula I. These processes form a further aspect of the present invention.

Compounds of formula I in which R4 and R $ together are a bond, may be prepared by dehydration of a compound of formula I, wherein R ₄ is hydroxy and R5 is H, for example in the presence of (a) sulfuric acid or (b) toluene -4-sulfonic acids and toluene.

Compounds of formula I in which R 3 is alkyl can be prepared by alkylating a compound of formula I in which R 3 is H, for example with an alkyl halide, optionally in the presence of a base, for example potassium carbonate, or by reductive alkylation with an aldehyde or ketone and formic acid, or with a reducing agent such as sodium cyanoborohydride, or by acylating a compound of formula I wherein R 3 is H, with an acylating agent such as an acyl halide, such as acetyl chloride, or with to some carboxylic anhydrides, for example acetic anhydride, and then by reaction with a reducing agent, for example boron methyl sulfide complex. Compounds of formula I in which R 3 is methyl can be prepared by methylation of a compound of formula I in which R 3 is H, for example using formaldehyde and formic acid. Compounds of formula I in which R 3 is ethyl can be prepared by acylation of a compound of formula I in which R 3 is H, for example, using acetic anhydride and then reduced by boron-methyl sulfide complex.

Compounds of formula I in which R _{3 is} alkenyl can be prepared by reaction of a compound of formula I in which R ₃ is H, for example with some alkenyl halide, optionally in the presence of a base, for example potassium carbonate.

Compounds of formula I in which R 3 is alkoxyalkyl can be prepared by reaction of a compound of formula I in which R 3 is H, for example with an alkoxyalkyl halide, optionally in the presence of a base, for example potassium carbonate.

Compounds of formula I in which R4 and Rg are both H can be prepared by reduction of a compound of formula I wherein R4 and Rg together represent a bond, with a suitable reducing agent, for example hydrogen in the presence of a 10% palladium on carbon catalyst, and in a suitable solvent such as ethanol.

Compounds of formula I wherein R4 is hydroxy and Rg is H may be prepared by reaction of a compound of formula II

with an organometallic agent, for example an organolithium compound of formula III ^R l ^Li III or a Grignard reagent of formula IV

RlMgX _Iv in which X is chloro, bromo or iodo, in a suitable solvent system, followed by hydrolytic treatment.

Compounds of formula II can be prepared by reaction of a compound of formula V

NR ₃ (CH ₂ ) _m .CHR ₂ .CO ₂ R ₇ in which R 8 and R 7 are the same or different and are alkyl groups containing 1 to 4 carbon atoms with a base, for example sodium alkoxide, to give the compound of formula VI which is then treated with an aqueous acid solution to give the compound of formula II.

Compounds of formula II can be prepared from compounds of formula V with the addition of a base, such as sodium alkoxide followed by the addition of an aqueous acid solution, without isolating the compounds of formula VI.

Compounds of formula V can be prepared by reaction of a compound of formula VII (MA

NHR,

CO ₂ R ₆

In II with the compound of formula VIII r ₇ o ₂ c .chr _2. (ch ₂ ^ z

In III wherein Z is a prominent group, for example chloro, bromo or iodo, the presence of a base, for example potassium carbonate.

Compounds of formula VII can be prepared by esterifying a compound of formula IX

with an alcohol of the formula RgOH, optionally in the presence of an acidic catalyst.

The therapeutic activity of the compounds of this invention is illustrated by the following tests performed on standard laboratory animals.

Test 1 - mice

The therapeutic activity of the compounds of formula I was demonstrated by evaluating the ability of the compounds to destroy the hypothermic effects of reserpine in the following manner. Male mice of the Charles River CDI strain, weighing between 18 and 30 g, were separated into groups of five and administered food and water ad libitum. After five hours, the body temperature of each mouse was orally measured and intraperitoneally injected with reserpine (10 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected was 10 ml / kg body weight. Nine hours after the start of the test, food was withdrawn and water was still available ad libitum. Twenty-four hours after the start of the test, the temperatures of the mice were measured and given orally to the test compound at a dose of 10 ml / kg body weight. The compound was administered in aqueous solution. after three hours, we again measured the temperatures of all mice. Next, we calculated the percentage of reservoir-induced loss of body temperature by the formula:

[(Temp. After 27 hours) - (Temp. After 24 hours)] x 100 (Temp. After 5 hours) - (Temp. After 24 hours)

The percentage of nullification for each group of five mice was determined at more than one dose to determine which dose produces 50% nullification (EDgg). Examples of compounds that gave EDgg values of 30 mg / kg or less are given in Table 1. It is understood by those skilled in the art that this test is indicative of compounds exhibiting anti-depressant activity in humans.

Test 2 - rats

The therapeutic activity of the compounds of formula I has been demonstrated by evaluating the ability of the compounds to prevent reserpine-induced eyelid sagging (eye closure) in the following manner. Male rats strain Charles

Rider CDs weighing between 140 and 180 g were randomly separated into five rats in each cage and given food and water ad libitum. Eighteen hours before the start of the test, four of the five rats were tagged with a pen so that each rat could be individually identified; then we took away our food. The next morning, two hours before the test, we determined the weight of the rats and used a semi-random code to schedule the treatment of rats. The test was initiated by oral administration either:

a) test compounds in solution in deionized water at a dose of 10 ml / kg body weight, followed immediately by an intravenous injection of 1 ml / kg body weight of reserpine (0.75 mg / kg) in a solution in deionized water containing 238 mM citric acid, 1.02% v / v Tween 80 and 0.2% v / v benzyl alcohol (treatment group);

b) deionized water at a dose of 10 ml / kg body weight, followed immediately by intravenous injection of 1 ml / kg body weight of reserpine (0.75 mg / kg) in a solution in deionized water containing 238 mM citric acid, 1.02% v / v Tween 80 and 0.2% v / v benzyl alcohol (control group); or

c) deionized water at a dose of 10 ml / kg body weight, followed immediately by an intravenous injection of 1 ml / kg body weight of deionized water containing 238 mM citric acid, 1.02% v / v Tween 80 and 0.2% v / v benzyl alcohol (negative control group).

Three hours later, the rats were individually placed in clean plexiglass boxes (42 x 22 x 22 cm) and then observed by a person who did not know how the individual animals were treated. The degree of eyelid sagging was recorded after 45 seconds and 75 seconds, with the observer using the following rating system: 0 = eyes fully open, 1 = eyes 1/4 closed, 2 = eyes 1/2 closed, 3 = eyes 3/4 closed, 4 = eyes completely closed. We then calculated the mean value of eyelid enlargement in all equally treated rats, which typically comprised a group of eight rats. Then, the mean eyelid enlargement of the negative control group was subtracted from the mean eyelid enlargement in the positive control group to obtain a measure of reserpine-induced eyelid enlargement in the absence of the test compound. The mean eyelid lengthening in each treatment group of rats was determined at more than one dose of test compound to obtain a dose (EDgg) that results in a 50% prevention of tl reserpin-induced eyelid lengthening. Examples of compounds that gave Εϋβθ values of 30 mg / kg or less were given in Table 1. It is understood by those skilled in the art that this test is indicative of compounds that exhibit anti-depressant activity in humans.

TABLE 1

Example no. Test 1 ED ₅₀ (mg / kg) Test 2 ED ₅₀ (mg / kg) 1 Inactive @ 30 11.3 2 -16 8.1 3 10.7 7.7 4 Inactive @ 30 2.2 5 -20 7.0 6 14.1 2.7 7, 23 2.0 1.4 8 16.4 5.1 9 -11 3.9 10 -18 8.5 11 -22 Inactive @ 30 12 11.9 11.9 13 3 Inactive @ 30 21.8

14 -12 30.0 15 6.9 3.8 16 9.4 3.3 17 -23 3.1 18 4.8 0.5 19 -14 5.8 20 -2 6 3.0 21 Inactive® 30 9.1 22 -30 10.1 24 -11.5 Inactive @ 30 25 Inactive® 30 9.9 26 Inactive® 30 5.6

The invention is illustrated by the following examples, which are given by way of example only. The final products of each of these cases were characterized by one or more of the following procedures: gas-liquid chromatography, elemental analysis, nuclear magnitude resonance spectroscopy and infra-red spectroscopy.

Example A

A mixture of 1-aminocyclohexanecarboxylic acid (62.4 g) and saturated ethanolic hydrochloric solution (400 ml) was heated under reflux for 7 hours and then allowed to stand at room temperature for 2 days. The mixture was again saturated with hydrogen chloride and refluxed for a further 23 hours. The solvent was then removed in vacuo and the residue was diluted with ice-water and basified by the addition of an excess of 5 M aqueous sodium hydroxide solution. The product was extracted into ether, the extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo to give ethyl 1-aminocyclohexanecarboxylate. Yield 50.6 g.

A mixture of ethyl 1-aminocyclohexanecarboxylate (37.1 g; prepared in the same manner as described above), potassium carbonate (37 g) and ethyl 4-bromobutyrate (42.3 g) was stirred at 100 ° C for 10 hours, cooled to room temperature temperature and diluted with ice-water. The product was extracted into ether and the extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo to give an oil (46.6 g). Unreacted ethyl 4-bromobutyrate was removed by distillation (64 ° C at 1.6 mbar) and the remaining ethyl 1- (3-ethoxycarbonylpropylamino) cyclohexanecarboxylate was used without further purification. Yield 30.5 g.

Sodium (8.9 g) was dissolved in ethanol (175 ml) and the solvent removed in vacuo. The residue was stirred at room temperature with ethyl 1 (3-ethoxycarbonylpropylamino) cyclohexanecarboxylate (52.2 g; prepared in the same manner as described above) and heated to 145 ° C with stirring while stirring the ethanol released into the mixture. reaction, removed by distillation. When ethanol release ceased, the residue was cooled to room temperature, diluted with water and acidified to pH 1 by the addition of concentrated hydrochloric acid. The solution was then basified by addition of an excess of solid potassium carbonate and the product extracted into ethyl acetate. The extracts were dried over magnesium sulfate and the solvent removed in vacuo to give ethyl 5-oxo-1-azaspiro [5.5] undecane-4-carboxylate. Yield 30.6 g.

A mixture of ethyl 5-oxo-1-azaspiro [δ.δ] undecane-4-carboxylate (13.9 g; prepared in the same manner as described above), concentrated hydrochloric acid (30 ml) and water (60 ml ) was heated at 90-96 ° C for δ hours. The solvent was removed in vacuo and the residue was diluted with ice-water (30 ml) and basified by addition of an excess of δ M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate and the extracts were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give 1-azaspiro [δ.δ] undecan-6-one as a pale brown solid. Yield 6.9 g, m.p. 25 ° C.

Example B

Sodium (9.4 g) was dissolved in ethanol (186 ml) and the solvent removed in vacuo. The residue was stirred at room temperature with ethyl 1 (3-ethoxycarbonylpropylamino) cyclohexanecarboxylate (62.7 g; prepared in a manner identical to that described in Example A) and the mixture was stirred at 160 ° C while stirring. The ethanol formed in the reaction was removed by distillation. When ethanol release ceased, the last traces of solvent were removed in vacuo to give a solid, cooled to room temperature, dissolved in a mixture of water (200 ml) and propan-2-ol (300 ml) and allowed to stand. room temperature for 48 hours. The solution was cooled in ice and acidified to pH 1 by the addition of concentrated hydrochloric acid. The mixture was then basified by addition of an excess of solid potassium carbonate and allowed to stand at room temperature for 24 hours. The product was extracted into ethyl acetate, the extracts were dried over magnesium sulfate and the solvent was removed in vacuo to give

1-azaspiro [δ.δ] undecan-6-one as a pale brown solid. Yield 20.6 g; m.p. 63 ° C.

Examples C to I

A compound of the formula RjMgBr, in which Rj is as defined in Table 2, was prepared by adding dropwise a solution of the compound of the formula RjBr (ag) in solvent (b ml) to the magnesium (cg) under nitrogen. ether (k) or tetrahydrofuran (1), or a mixture thereof, initially at room temperature and then at exothermic reaction, at reflux temperature. After the addition was complete, the mixture was stirred at room temperature for d hours.

A solution of 1-azaspiro [5.5] undecan-5-one (eg) in a solvent that was ether (f 'ml), tetrahydrofuran (f ml) or a mixture thereof was added dropwise to a solution of RjMgBr while stirring at 0 ° C. . The mixture was stirred for hours at room temperature in C to G and at reflux in H and I. The reaction mixture (if necessary cooled) was then quenched by carefully adding saturated aqueous ammonium chloride solution. The product was extracted into ethyl acetate and the extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo.

The crude product was purified by the procedures identified in the column titled Nb to give compounds of structure I wherein R4 is hydroxy and Rg is H (h g).

Comments on Table 2

In the column titled Soil. (° C) means letters ND that have not been determined.

2.1. The crude product was triturated with petroleum ether (boiling point 40-60 ° C) to give the free base as a solid.

2.2. The crude product was triturated with ethyl acetate to give the free base as a solid.

2.3. Low-boiling impurities were removed by distillation in vacuo at 100 ° C and 0.6 mbar to leave a brown oil. The oil was triturated with ethyl acetate to give the free base as a solid.

2.4 The crude product was triturated with ethyl acetate for three hours to give a solid which was further purified by high performance preparative liquid chromatography (HPLC) through silica gel using methanol as eluent. Suitable fractions were combined and the solvent removed in vacuo to give the free base as a solid.

TABLE

H U (tf 0 P 143-145 128-130 Ω 2 170- 171.5 Ω 2 Ω 2 Ω 2 X! 2 τ ~ Η CN CN CN ΓΟ ΓΟ (Ν (Ν CN CN m (Ν CN X ro io σι C0 ΓΟ sr ιη ιη m ο ο 7-1 and tH m σ C0 γο Ο (Ν CN G) sr co LT) CN co sr CN CN <Ν CN U-l o Ο Ο Γ — 1 Ο co ο Γ0 o CO., LTD Ο Ο ΐ ~ ί ο Γ ~ U-l Mr σ Ο m ο ο o Γ0 ο ο Φ T-1 γω rH ο ιη co co ιη (Ν o CO., LTD ο ο τ ~ Η C0 <0 Ό and o LT) Ο ιη rH ιη CN o r ~ 1 ιη ο ο χΗ U co σ sr C0 Ρ σ \ m σ σ r-4 Γ0 C0 ΓΩ ΓΩ CN Lt γω - co X CN σ vi σ - ο 00 Ρ ΤΗ - m - γω f-i about - about you 7-1 - ' ο - ο —G You Ο Ρ 7-1 '7-1 ο -. ο Ο You ο γ— { 7-1 7-1 <0 Γ- σ m ΓΟ sr t — 1 C0 m 'Ι> m CO., LTD and m ^J cn t — 1 C0 ΓΩ Ο C0 C0 Γ- ΓΟ rH X 1 0 M 0 P ι — 1 · Η 24 β φ si »P 1 0 Η 0 Ρ · · Η 24 β 'Φ m p 1 0 Ή 24 r — ι • Η · Η Ό β Φ SJI ρ «· 0 Π Η ι 0 Μ 0 3 Ρ · Η 4-1 β • Φ si »Ρ r4 ι · Η φ β ε φ • Η 0 4-1 Η Η> Ρ 0 3 Ρ ¹ Ρ Ρ ΓΟ P Ρ ι • Η η 24 0 Ρ ΓΗ · · Η Β C • Φ sj «Ρ Ρ • Η Ρ Ρ (0 β I ΓΟ • · H P Λ ΧΛ υ Ω ω tli Ο X Η

Example J

4-Chlorophenylmagnesium bromide was prepared under nitrogen by adding dropwise a solution of 4-bromochlorobenzene (20.35 g) in ether (160 ml) dropwise to metallic magnesium (2.6 g) and initially at room temperature after the exothermic reaction began, at reflux temperature. After the addition was complete, the mixture was stirred at room temperature for 1 hour.

The solution was then warmed to reflux while stirring, and a solution of l-azaspiro [5.5jundecan-5-one (9.7 g; prepared as described in Example A) in toluene (160 ml) was added dropwise. the ether was removed by distillation until the internal temperature increased to about 95 ° C. The mixture was then heated at reflux for 2 hours, allowed to cool to room temperature and then quenched by the addition of an excess of saturated ammonium chloride solution. The product was extracted into ethyl acetate (3 x 300 ml) and the extracts were combined and dried over magnesium sulfate. The solvent was removed in vacuo and the residue triturated with ethyl acetate. The resulting solid was collected by filtration, washed with ethyl acetate and dried in vacuo at room temperature to give 5- (4-chlorophenyl) -5-hydroxy-1-azaspiro [δ.δ] undecane as a white solid. Yield 6.7 g; m.p. Mp 158-164 ° C.

Examples 1 to 3

The compounds of formula I prepared in Examples C to E were converted to their hydrochloride salts by saturating the ether solutions of the compounds with hydrogen chloride. The melting points of the resulting hydrochloride salts are given in Table 3.

TABLE 3

Example no. Source material m.p. (° C) 1 C > 250 (breakup) 2 D 294-295 (breakup) 3 E 307 (breakup)

Example 4

A mixture of 5- (4-chlorophenyl) -5-hydroxy-1-azaspiro [5.5 jundecane (3 g; prepared as described in Example C) and acetic anhydride (45 ml) was heated at 90-95 ° C over 16 hours Excess acetic anhydride was removed in vacuo and the residue triturated with ether to give a solid which was collected by filtration. The filtrate was allowed to stand at room temperature for 1 hour, thereby accelerating the further deposition of the solid collected by filtration.

The mixture of combined solids (2.3 g) and tetrahydrofuran (21 ml) was heated at reflux under nitrogen and the boron-methyl sulfide complex (2.3 g) was added dropwise over 35 minutes, and dimethyl sulfide was removed by distillation. After complete addition, the mixture was heated at reflux for 4.5 hours and then the solvent was removed in vacuo and the residue was heated to 100 ° C. 5 M hydrochloric acid (1.5 ml) and water (12.4 ml) were added and the solution heated at 100 ° C for 45 minutes. The mixture was then cooled to room temperature and a 5 M aqueous solution of sodium hydroxide (2.4 ml) was added.

The solution was then saturated with solid potassium carbonate and the product extracted into ether. The extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo to give an oil (1.7 g). The oil was combined with a further oil (0.4 g; prepared in the same manner) of the same purity and purified by flash chromatography on silica gel using a 9: 1 mixture of dichloromethane and ethyl acetate as eluent. The appropriate fractions were combined, the solvent removed in vacuo and the resulting oil (1.9 g) distilled to give an oil. Yield 1.3 g; boil. 150155 ° C at 0.4-0.5 mbar.

The oil (1.3 g) was dissolved in ether (20 ml) and the solution was saturated with hydrogen chloride. The solvent was removed in vacuo and the residue triturated with a mixture of dichloromethane and ether. The resulting solid was collected by filtration and dried in vacuo at room temperature to give 5- (4-chlorophenyl) -1-ethyl-5-hydroxy-1-azaspiro [5.5] undecane hydrochloride as a gray-white solid. Yield 0.6 g; m.p. Mp 146-148 ° C.

Example 5

5- (4-Chlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane (5.9 g; prepared as described in Example C) was dissolved in concentrated sulfuric acid (75 ml) and stirred at room temperature. 3 hours. The mixture was then slowly poured into ice-water (300 ml) and the resulting solid collected by filtration, washed with a little water and dried in vacuo at room temperature over phosphorus pentoxide to give 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-one sulfate, as a white solid. Yield 6.2 g; m.p. 228-233 ° C.

Example 6

A mixture of 5- (4-chlorophenyl) -1-azaspiro [5.5 ^; undec-4-ene sulphate (0.5 g; prepared as described in Example 5) and water (5 ml) was stirred at room temperature to obtain a initially moving suspension which rapidly thickened. Water (5 ml) was added to facilitate mobility, and the solid was collected by filtration, washed with water (5 ml) and dried in vacuo at room temperature to give 5- (4-chlorophenyl) -123 azaspiro [ 5.5) undec-4-ene 0.5 sulfate, 2.1 hydrate, as a white solid. Yield 0.3 g; m.p. 205-215 ° C.

Example 7

Suspension of 5- (4-chlorophenyl) -1-azaspiro [5.5j undec-4-ene sulfate (13 g, prepared in the same manner as described in Example 5) and 1 M aqueous sodium hydroxide solution (200 ml) was stirred at room temperature for 1 hour and then the free base was extracted into ether (3 x 150 ml). The extracts were combined, dried over magnesium sulfate, concentrated to a volume of 150 ml and filtered. The filtrate was collected in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature for 24 hours and at 60 ° C for 8 hours to give 5- (4-chlorophenyl) -1-azaspiro [5.5] undek4-ene hydrochloride, as a white solid. Yield 8.6 g; mp> 300 ° C.

Example 8

5- (3-chlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane (2.5 g prepared as described in Example D) was dissolved in concentrated sulfuric acid (35 ml) and at room temperature stirred for 2 hours. The mixture was then carefully poured onto ice (100 ml) and the resulting white precipitate was collected by filtration and suspended in ethyl acetate (300 ml). A 5 M aqueous solution of sodium hydroxide (250 ml) was added and the mixture was stirred at room temperature for 15 minutes. The aqueous layer was separated and extracted with ethyl acetate (2 x 200 mL), then the combined organic solutions were washed with water, dried over magnesium sulfate and the solvent removed in vacuo. The resulting oil was dissolved in ether (100 ml), charcoal (1 g) was added and the mixture was heated at reflux for 5 minutes and filtered warmly. The cooled filtrate was saturated with hydrogen chloride and the resulting solid was collected, washed with ether and dried in vacuo at room temperature to give 5- (3-chlorophenyl) 1-azaspiro [5.5andeuk-4-one hydrochloride as a white solid. Yield 2.1 g; m.p. 281-282 ° C (decomposition).

Example 9

5- (3,4-Dichlorophenyl-5-hydroxy-1-azaspiro; 5.5 andecane (3.0 g; prepared as described in Example E) was dissolved in concentrated sulfuric acid (35 ml) and stirred at room temperature for 4 hours and then the mixture was carefully poured onto ice (100 ml), the resulting white precipitate was collected by filtration and suspended in 5 M aqueous sodium hydroxide solution (200 ml), the mixture was stirred at room temperature for 15 minutes, and then the product was extracted into ether. (2 x 250 ml) The combined extracts were washed with water, dried over magnesium sulfate and filtered The filtrate was cooled in ice, saturated with hydrogen chloride and the resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature 5- (3,4-Dichlorophenyl) -1-azaspiro [δ.5] undec-4-ene hydrochloride was obtained as a white solid, yield 2.5 g; mp 332 ° C (decomposition).

Example 10

5- (4-Fluorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane (1.27 g; prepared in the same manner as described in Example F) was dissolved in concentrated sulfuric acid (25 ml) and stirred at room temperature. The solution was carefully poured onto ice (50 ml) and the sticky solid collected by filtration. The solid was triturated with ether (2 x 50 ml), collected by filtration, washed with ether and dried in vacuo at room temperature to give a solid triturated with hot ether (70 ml), collected by filtration. washed with ether and dried in vacuo at 60 ° C to give 5- (4-fluorophenyl) -1-azaspiro [5.5jundec-4-one sulfate as a white solid. Yield 1.3 g; m.p. Mp 195-200 ° C.

Example 11

5-Hydroxy-5- [3- (trifluoromethyl) phenyl] -1-azaspiro [5.5] undecane (2.2 g; prepared as described in Example G) was dissolved in concentrated sulfuric acid (25 ml) and stirred at room temperature. temperature for 4 hours. The mixture was carefully poured onto ice (100 ml) and the resulting white precipitate was collected by filtration and suspended in 5 M aqueous sodium hydroxy25 da (250 ml). The mixture was stirred at room temperature for 15 minutes and then the product was extracted into ethyl acetate (2 x 125 ml). The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo. The resulting oil was dissolved in ether and the solution filtered. The filtrate was cooled in ice, saturated with hydrogen chloride, and the resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature to give 5- [3- (trifluoromethyl) phenyl 1-1-azaspiro [5.51 undec-4 -en hydrochloride, as a white solid. Yield 1.0 g; m.p. > 250 ° C (sublimates).

Example 12

A mixture of 5-hydroxy-5- (2-naphthyl) -1-azaspiro [5.5] undecane (2.1 g; prepared as described in Example I), p-toluenesulfonic acid (1.62 g) and toluene (500 ml) ) was refluxed for 20 hours and the reaction water was removed by azeotropic distillation (DeanStark apparatus). Toluene (500 ml) and p-toluenesulfonic acid (2.4 g) were added and reflux was continued for 35 hours. The cooled mixture was poured into 5 M aqueous sodium hydroxide solution (500 ml) and stirred vigorously for 5 minutes. Ethyl acetate (250 ml) was added and stirring was continued for 5 minutes. The aqueous layer was separated and further extracted with ethyl acetate (2 x 500 ml). The organic solutions were combined, washed with water, dried over magnesium sulfate and the solvents removed in vacuo to give an oil. This oil was purified by flash chromatography on silica gel using toluene / triethylamine (95: 5) as eluent. Suitable fractions were combined and the solvents were removed in vacuo. The resulting oil was dissolved in ether, the solution filtered and the filtrate cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature to give 5 (2-naphthyl) -1-azaspiro [δ.δ] undec-4-ene hydrochloride as a white solid. Yield 1.8 g; m.p. 297-302 ° C.

Example 13

A mixture of 5-hydroxy-5- (4-methoxyphenyl) -1-azaspiro [5.5] undecane (2.8 g; prepared as described in Example H), p-toluenesulfonic acid (2.3 g) and toluene ( 150 ml) was heated at reflux for 17 hours and the reaction water was removed by azeotropic distillation (Dean-Stark apparatus). The cooled mixture was poured into 5 M aqueous sodium hydroxide solution (500 ml) and stirred vigorously for 5 minutes. Ethyl acetate (250 ml) was added and stirring was continued for 5 minutes. The aqueous layer was separated and further extracted with ethyl acetate (2 x 500 ml). The organic solutions were combined, washed with water, dried over magnesium sulfate and the solvents removed in vacuo to give an oil. This oil was dissolved in ether, the solution filtered and the filtrate cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature to give 5- (4-methoxyphenyl) -1-azaspiro [5.5j undec-4-ene hydrochloride as a white solid. Yield 2.7 g; m.p. 257-266 ° C (decomposition).

A mixture of 5- (4-methoxyphenyl) -1-azaspiro [5.5'undek-4-ene hydrochloride (1.0 g), glacial acetic acid (20 ml) and hydrobromic acid (48%, 20 ml) was heated at reflux for 6 hours. 5 hours and then allowed to cool. The mixture was neutralized by the addition of saturated aqueous sodium hydrogen carbonate solution and the product extracted into ether (3 x 100 ml). The extracts were combined, dried over magnesium sulfate and the solvent removed in vacuo to give a solid which was purified by flash chromatography on silica gel using toluene / triethylamine eluent (4: 1). Suitable fractions were combined, the solvents were removed in vacuo and the resulting product was dissolved in ether. The solution was filtered and the filtrate cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature to give 5 (4-hydroxyphenyl) -1-azaspiro [5.5 undec-4-ene hydrochloride as a white solid. Yield 0.7 g; m.p. 285-295 ° C.

Example 14

5- (4-Chlorophenyl) -5-hydroxy-1-azaspiro [5.5; undecane (5.1 g; prepared in the same manner as described in Example C) was dissolved in concentrated sulfuric acid (70 ml ) and stirred at room temperature for 4 hours. The mixture was poured onto ice (300 ml) and the resulting solid was collected by filtration, suspended in water (150 ml) and basified with up to 27 ml of 5 M aqueous sodium hydroxide solution. The resulting solid, 5 (4-chlorophenyl) -1-azaspiro [5.5 {undec-4-ene), was collected by filtration and dried in vacuo at room temperature.

A mixture of solids (4.5 g) and ethyl formate (300 ml) was refluxed for 48 hours. The mixture was concentrated in vacuo to a small volume and the resulting solid was collected by filtration and crystallized from ethyl acetate (60 ml) (the hot solution was decolorized with charcoal) to give 5- (4-chlorophenyl) -1-azaspiro [5.5 undek-4-one formate as a white solid solution. Yield 1.7 g; m.p. Mp 136-140 ° C.

A mixture of 5- (4-chlorophenyl) -1-azaspiro [5.5i undec-4-one formate (1.7 g), formic acid (15 ml) and 37-40% aqueous formaldehyde (30 ml) was heated at ca. 95 ° C for 7.5 hours and then cooled in ice. The mixture was basified by the addition of 5 M aqueous sodium hydroxide solution and the product was extracted into ethyl acetate (2 x 150 ml). The extracts were combined, dried over magnesium sulfate, and the solvent removed in vacuo to leave an oil that slowly solidified at room temperature. The solid was triturated with ether and the mixture filtered. The filtrate was evaporated to leave an oily residue which was dissolved in ether, dried over magnesium sulfate, and the solvent removed in vacuo to leave an oil which slowly solidified at room temperature. Yield 1.3 g.

The solid was dissolved in ether (80 ml), the solution filtered and the filtrate cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at 70 ° C to give 5- (4-chlorophenyl) -1-methyl-1-azaspiro [5.5; undec-4-one hydrochloride as a white solid. Yield 1.2 g; m.p. 243-248 ° C (decomposition).

Example 15

A solution of formic acid (0.4 g) in methanol (35ml) was added to a solution of 5- (4-chlorophenyl-1-azaspiro [5.5j undec-4-one (1.0 g; prepared in a manner identical to that of we described it in the example

14) in ether (25 ml). The solvents were removed in vacuo and the residue triturated with ether to give a white solid which was collected by filtration and dried in vacuo at room temperature to give 5- (4-chlorophenyl) 1-azaspiro [5.5! undek-4-one fumarate as a white solid. Yield 1.1 g; m.p. 175-180.5 ° C (decomposition).

Example 16

A solution of methanesulfonic acid (0.3 g) in ether (15 ml) was added dropwise to a cooled solution of 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene (0.8 g; prepared in the same manner to that described in Example 14 in ether (25 ml). The resulting solid was collected by filtration, washed with ether and dried in vacuo to give 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene methanesulfonate as a white solid. Yield 1.0 g; m.p. Mp 226-231.5 ° C.

Example 17

A mixture of 1-aminocyclopentanecarboxylic acid (50.0 g) and saturated hydrochloric ethanol solution (350 ml) was refluxed for 6 hours. The mixture was cooled, the solvent was removed in vacuo and the residue was diluted with water (150 ml). The resulting solution was basified by the addition of excess 5 M aqueous sodium hydroxide solution and the product extracted into ether. The extracts were dried over magnesium sulfate and the solvent removed in vacuo to give ethyl 1-aminocyclopentanecarboxylate. Yield 19.6 g.

The aqueous phase was acidified with 5 M hydrochloric acid and the solvent removed in vacuo. The solid was mixed with saturated ethanol hydrochloric solution (230 ml) and the mixture refluxed for 6 hours. The mixture was cooled, the solvent removed in vacuo and the residue was diluted with cold water (100 ml). The mixture was basified by the addition of 5 M aqueous sodium hydroxide solution and the product extracted into ether. The extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo to give ethyl 1-aminocyclopentanecarboxylate. Yield 24.3 g. ⁵

A mixture of ethyl 1-aminocyclopentanecarboxylate (43.9 g), potassium carbonate (47.8 g) and ethyl 4-bromobutyrate (54.5 g) was stirred at 100 ° C for 10 hours, cooled to room temperature and diluted with ice. water. The product was extracted into ether and the extracts were washed with water, dried over magnesium sulfate and the solvent removed in vacuo to give an oil (61.1 g) which was distilled to give ethyl 1- (3-ethoxy-carbonylpropylamino) cyclopentanecarboxylate as a colorless oil. Yield 49.5 g; boil. 109-124 ° C at 0.6 mbar.

Sodium (8.4 g) was dissolved in ethanol (170 ml) and the solvent was removed in vacuo. The residue was stirred at room temperature with ethyl 1- (3-ethoxycarbonylpropylamino) cyclopentanecarboxylate (49.5 g) and the mixture heated to 100 ° C while stirring, while the ethanol formed in the reaction was removed by distillation. When ethanol release ceased, the residue was dissolved in hot propan-2-ol (150 ml). The solution was cooled to room temperature, diluted with water and acidified to pH 1 with the addition of concentrated hydrochloric acid. The solution was then basified by addition of an excess of solid potassium carbonate and the product extracted into ethyl acetate. The extracts were dried over magnesium sulfate and the solvent removed in vacuo to give ethyl 10-oxo-6-azaspiro [4.5] decane-9-carboxylate. Yield 7.6 g.

A mixture of ethyl 10-oxo-6-azaspiro [4.5] decane-9-carboxylate (7.6 g), concentrated hydrochloric acid (35 ml) and water (35 ml) was heated at 90-95 ° C for 8 hours. The solvent was removed in vacuo and the residue was diluted with ice-water (35 ml) and basified by addition of an excess of 5 M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate and the extracts were washed with brine, dried over magnesium sulfate and the solvent removed in vacuo to give 6-azaspiro [4.5] decan-10-one. Yield 3.1 g.

4-Chloromagnesium bromide was prepared by adding dropwise a solution of 4-bromochlorobenzene (9.6 g) in ether (55 ml) dropwise to the metal magnesium (1.2 g), initially at room temperature and then at room temperature. the exothermic reaction began, at reflux temperature. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. A solution of 6-azaspiro [4.5decan-10-one (3.1 g; prepared as described above) in ether (25 ml) was added dropwise at 0 ° C and the mixture stirred at room temperature for 24 hours. The reaction was quenched by slowly adding an excess of saturated aqueous ammonium chloride solution and the resulting solid was collected by filtration. The solid was suspended in water and basified by the addition of an excess of 5 M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (3 x 100 mL), the extracts were dried over magnesium sulfate and the solvent removed in vacuo to give 10- (4-chlorophenyl) -10-hydroxy-6-azaspiro [4.5 ^ decane as a gray-white solid. Yield 1.6 g; m.p. Mp 152-155 ° C.

10- (4-Chlorophenyl) -10-hydroxy-6-azaspiroj 4.5.5 decane (1.6 g) was dissolved in concentrated sulfuric acid (18 ml) and stirred at room temperature for 1.5 hours. The mixture was carefully poured onto ice-water (35 ml), stirred at 0 ° C for 1 hour and allowed to stand at 4 ° C for 24 hours. The product was collected by filtration, washed with water and dried in vacuo at room temperature to give 10- (4-chlorophenyl) -6-azaspiro [4.5] dec-9-one sulfate as a gray-white solid. Yield 1.7 g; m.p. 184-190 ° CPr 18

A mixture of 5- (4-chlorophenyl) -1-azaspiroph'5.5] undec-4-ene (2.8 g; obtained by calcining the hydrochloride salt prepared as described in Example 7), 10% platinum catalyst on carbon (0.24 g), ethanol (50 ml) and 2.5 M hydrochloric acid (10 ml) were hydrogenated at 1,013 bar and room temperature until hydrogen suction ceased (2.5 hours), then the mixture was filtered to remove spent catalyst and solvents removed in vacuo.

The residue was purified by flash chromatography on silica gel using a 9: 1 mixture of toluene and triethylamine containing an ethanol trace as eluent. Appropriate fractions were combined and the solvents removed in vacuo to leave a solid (2.3 g). The solid was suspended in propan-2-ol (25 ml) and the mixture heated at reflux, filtered while still hot and allowed to cool. The resulting solid was collected by filtration and dried in vacuo to give a white solid (0.24 g). Concentrating the liquid gave the second part of a white solid (0.46 g)

The solids were combined, dissolved in ether (35 ml) and the solution was saturated with hydrogen chloride. The resulting solid was collected by filtration and dried in vacuo at 95 ° C to give 5- (4-chlorophenyl) -1-azaspiro [δ.5 undecane hydrochloride as a white solid. Yield 0.6 g; m.p. 311312 ° C (softens at 299 ° C).

Example 19 r

A mixture of 5- (4-methoxyphenyl) -1-azaspiro [5.5: undec-4-ene hydrochloride (0.6 g; prepared as described in Example 13), catalyst for 10% palladium on charcoal (0.18 g) , ethanol (40 ml) and water (20 ml) were hydrogenated at 1,013 bar and room temperature until hydrogen suction ceased. The mixture was filtered to remove the catalyst and then the solvents were removed in vacuo to leave a white solid (0.6 g). The solid was triturated with ether (25 ml), collected by filtration and dried in vacuo to give 5- (4-methoxyphenyl) -1-azaspiro [5.5 · undecane hydrochloride as a white solid. Yield 0.5 g; m.p. 287-289 ° C (jumps at 285 ° C).

Example 20

A mixture of 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene hydrochloride (2.0 g; prepared as described in Example 7), 1-bromopropane (1 ml), potassium carbonate (2 , 0 g) and dimethylformamide (10 ml) were stirred at room temperature for 24 hours and at 95 ° C for 24 hours. Bromopropane (1 ml) and a catalytic amount of potassium iodide (10 mg) were added and stirring continued for 24 hours. Bromopropane (1 ml) was added and stirred at 95 ° C for a further 24 hours.

The mixture was cooled to room temperature, diluted with 1 M aqueous sodium hydroxide solution (100 ml) and the product extracted into ethyl acetate (3 x 50 ml). The extracts were combined, washed with water (2 x 30 ml), dried over magnesium sulfate and the solvent removed in vacuo to leave a brown oil. The oil was dissolved in ether (50 ml) and the solution was saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at room temperature to give 5- (4-chlorophenyl) -1-propyl-1-azaspiro [5.5] undec-4-ene hydrochloride as a gray-white solid . Yield 1.9 g; m.p. 245-246 ° C (jumps at 230 ° C).

Example 21

A mixture of 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene hydrochloride (2.0 g; prepared as described in Example 7), potassium carbonate (2.0 g), allyl bromide (2.9 ml) and dimethylformamide (25 ml) were stirred at 95 ° C for 17 hours and then allowed to cool to room temperature. The mixture was diluted with water (60 ml) and basified with the addition of 5 M aqueous sodium hydroxide solution (50 ml), then the product was extracted into ethyl acetate (3 x 100 ml). The extracts were combined, dried over magnesium sulfate, and the solvent removed in vacuo to leave a brown oil which was purified by flash chromatography on silica gel using a mixture of dichloromethane and industrial methylated spirit as a 99: 1 eluent. Appropriate fractions were combined and the solvents were removed in vacuo to leave a yellow oil (1.4 g) which was dissolved in ether (50 ml). The solution was filtered and added to an ice-cold solution of maleic acid (0.53 g) in ether (150 ml). The resulting solid was collected by filtration, washed with ether and dried in vacuo at 50 ° C to give 1-allyl-5- (4-chlorophenyl) -1-azaspiro [δ.δ] undec-4-en maleate, as a white solid. Yield 1.2 g; m.p. 130-133 ° C (jumps at 125 ° C).

Example 22

A mixture of 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene (1.5 g; obtained by basifying the hydrochloride salt prepared as described in Example 7) of potassium carbonate (1 , 6 g), 2-methoxyethyl bromide (2.7 ml) and dimethylformamide (28 ml) were stirred at 95 ° C for 67 hours and allowed to cool to room temperature. The mixture was diluted with 1 M aqueous sodium hydroxide solution (150 ml) and the product extracted into ethyl acetate (2 x 150 ml). The extracts were combined, washed with water (2 x 100 ml), dried over magnesium sulfate and the solvent removed in vacuo to leave a yellow oil (1.6 g). The oil was combined with another sample (0.2 g; prepared in the same manner) and purified by flash chromatography on silica gel using a 95: 5 mixture of toluene and triethylamine as eluent. Suitable fractions were combined and the solvents removed in vacuo to leave an oil which was dissolved in ether (50 ml). The solution was cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at 50 ° C for 7 hours to give 5- (4-chlorophenyl) -1- (2-methoxyethyl) -1-azaspiro [5.5] undec. 4-en

1,25 hydrochloride as a white solid. Yield 0.7 g; m.p. 135 ° C (decomposition) (softens at 95-100 ° C).

Example 23

At 0-5 ° C, ethanol (4 L) was saturated with hydrogen chloride for 4 hours. 1-Aminocyclohexanecarboxylic acid (600 g) was added to one portion and the mixture was stirred and refluxed for 8 hours, then allowed to stand at room temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in ice-water (1 L) and made basic at 0-5 ° C to pH 8-9 by the addition of 2 M aqueous sodium hydroxide solution. The product was extracted into dichloromethane (4 x 300 ml) and the extracts were combined and dried over sodium sulfate. The aqueous residues were basified to pH 10 by the re-addition of 2 M aqueous sodium hydroxide solution and the further product extracted into dichloromethane (4 x 200 ml). The extracts were combined and dried over sodium sulfate. The dry dichloromethane extracts were combined and the solvent removed in vacuo to leave ethyl 1-aminocyclohexanecyclocarboxylate as a light yellow oil. Yield 669 g.

A mixture of ethyl 1-amine kiohexanecarboxy late (669 g), potassium carbonate (683.1 g) and ethyl 4-bromobutyrate (558 ml) was stirred at 130 ° C for 18 hours, then cooled to room temperature and poured onto ice-water. (3 1). The product was extracted into dichloromethane and the combined extracts were dried over sodium sulfate and the solvent removed in vacuo to give ethyl 1- (3-ethoxycarbonylpropylamino) -cyclohexanecarboxylate as a brown / orange oil. Yield 943, 2 g.

Sodium (8.92 g) was dissolved in ethanol (150 ml) and the solvent removed in vacuo. Ethyl 1- (3-ethoxycarbonylpropylamino) 34 cyclohexanecarboxylate (50 g) was added and the mixture was stirred at 140 ° C, while the ethanol formed in the reaction was removed by distillation. When ethanol release ceased, the mixture was allowed to cool to room temperature to give an orange foam. A solution of concentrated hydrochloric acid (150 ml) in water (150 ml) was added and the mixture was heated at 95 ° C for 7 hours. Charcoal was added and the mixture filtered (hot) through celite, cooled to room temperature, washed with ethyl acetate (2 x 150 ml) and basified at 20 ° C with the addition of 5 M aqueous sodium hydroxide solution. The product was extracted into dichloromethane (5 x 250 ml) and the combined extracts washed with water (200 ml), dried over sodium sulfate and the solvent removed in vacuo to give 1-azaspiro [5.5] undecan-5-one as a grayish brown solid. Yield 18.6 g.

The reaction was repeated twice more, with the following reactants:

sodium (159.3 g) ethanol (1500 ml) ethyl 1- (3-ethoxycarbonylpropylamino) cyclohexanecarboxylate (447 g);

Then concentrated hydrochloric acid (1000 ml) water (1000 ml).

Total combined profit 245.11 g.

For 45 minutes, a solution of 1azaspiro [5.5] undecan-5-one (132.5 g) in toluene (1900 ml) was added under nitrogen and stirring with 4-chlorophenylmagnesium bromide (1 M solution in ether; 1904 ml). The ether solvent was removed by distillation at a rate equal to the addition of the toluene solution. After complete addition, the mixture was stirred at 95 ° C for another 3 hours, cooled to 20 ° C and quenched by the addition of saturated aqueous ammonium chloride solution (1 L). The mixture was filtered through celite and the filter layer was washed with water and ethyl acetate. The filtrate was separated and the aqueous layer was extracted with ether. The combined organic solutions were washed with water (500 ml) and the product extracted into 5 M hydrochloric acid (4 x 250 ml). This caused it to sediment some of the hydrochloride salt of the product; the solid was collected by filtration and washed with ethyl acetate. The filtrate was separated and the aqueous layer was washed with ethyl acetate, combined with a solid hydrochloride salt and basified by the addition of 5 M aqueous sodium hydroxide solution. The product was extracted into dichloromethane and the combined extracts were washed with water, dried over sodium sulfate and the solvent removed in vacuo to give a pale yellow solid (136.6 g). The solid was triturated with petroleum ether (boiling point 40-60 ° C) (500 ml) to give a solid which was collected by filtration and dried in vacuo to give 5- (4-chlorophenyl) -5- hydroxy-l-azaspiro [5.5jundecane, as a light cloudy yellow solid. Yield 105.2 g.

The reaction was repeated using:

4- Chlorophenylmagnesium bromide (1 M ether solution, 1618 ml)

1-Azaspiro 5.5 undecan-5-one (112.6 g) toluene (1.6 L) aqueous ammonium chloride solution (1 L), although the treatment was different: after cooling with ammonium chloride solution, the mixture was filtered through celite and separated the layers. The aqueous layer was extracted twice more with ethyl acetate and the combined organic solutions were dried over sodium sulfate and the solvents were removed in vacuo to leave an oil. The cake on the celite filter was boiled in ethyl acetate and the mixture was hot filtered through celite. The filtrates were combined with oil and the solvent removed in vacuo. The residue was triturated with ice-cold petroleum ether (boiling point 60-80 ° C) (1000 ml) to give a solid which was collected by filtration and dried in vacuo to give 5- (4-chlorophenyl) -5 -hydroxy-l-azaspiro [5.5 iundecane as a greyish brown solid. Yield 129.5 g.

5- (4-chlorophenyl) -5-hydroxy-1-azaspiroi 5.5 Iundecane (105.1 g) was added concentrated sulfuric acid (600 ml) over 20 minutes while vigorously stirring, then the mixture was stirred at room temperature for a further 1 hour and poured it carefully onto ice (21), which resulted in the sedimentation of the white solid. The mixture was cooled on ice for 2 hours and the solid was collected by filtration. The solid was basified by the addition of excess 5 M aqueous sodium hydroxide solution and the product was extracted into ether (4 x 200 ml) followed by dichloromethane (2 x 250 ml). The extracts were combined, dried over sodium sulfate, and the solvents removed in vacuo to give 5- (4-chlorophenyl) -1-azaspiro | 5.5 junk-4-ene as a cloudy yellow solid. Yield 98 g.

The reaction was repeated using 5- (4-chlorophenyl) -5-hydroxy-1-azaspiro 15.51 undecane (129.5 g) and concentrated sulfuric acid (600 ml). Yield 122.5 g.

To a solution of 5- (4-chlorophenyl) -1-azaspyrrole 5.5 undec-4-ene (98 g) in ether (1 L), 5 M hydrochloric acid (200 ml) was slowly added and the mixture was stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and washed with cold water and then with dichloromethane to give a gray-white solid. The process was repeated using 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-one residue to give an off-white solid. The combined solids were stirred in dichloromethane (1 L) for 1 hour, collected by filtration, washed with dichloromethane (200 ml) and dried in vacuo to give 5- (4-chlorophenyl) -1-azaspiro [5.5j undec. 4-hydrochloride as a gray-white solid. Yield 224.3 g; m.p. > 300 ° C.

Example 24

Magnesium metal (3.8 g) was initially added at room temperature and then, at exothermic reaction, at reflux temperature, a solution of 2-bromochlorobenzene (36.7 ml) in ether (260 ml) was added dropwise. . After the addition was complete, the mixture was stirred at room temperature for 1 hour. A solution of 1azaspiro 5.5 undecan-5-one (12.5 g; prepared as described in Example B) in tetrahydrofuran (200 ml) was added at room temperature, then the mixture was stirred and refluxed for 18 hours. The mixture was cooled to room temperature and quenched by the addition of an excess of saturated aqueous ammonium chloride solution, and then the product was extracted into ethyl acetate (2 x 300 ml). The extracts were combined, dried over magnesium sulfate and the solvents removed in vacuo to give a brown oil (46.7 g). The low boiling point impurities ¹ were removed by distillation at <100 ° C at about 13.3 mbar. The residue, a viscous, brown oil, was triturated in ethyl acetate to give a light gray solid, which was collected by filtration and dried at atmospheric pressure. Yield 0.17 g. The filtrate was allowed to concentrate at atmospheric pressure to give two more portions of a light gray solid (0.11 g + 0.47 g). The three solids were combined to give 5-hydroxy-5-phenyl-1-azaspiro [5.5jundecane, as a light gray solid. Yield 0.75 g.

A mixture of 5-hydroxy-5-phenyl-1-azaspiro [5.5] undecane (0.75 g), ptoluenesulfonic acid (1.1 g) and toluene (340 ml) was heated under stirring for 96 hours while stirring water. which was formed in the reaction was removed by azeotropic distillation. P-toluenesulfonic acid (2.2 g) was added and reflux was continued for 144 hours. The mixture was allowed to cool to room temperature and was quenched by the addition of an excess of 5 M aqueous sodium hydroxide solution. The product was extracted into toluene and the extracts combined, dried over magnesium sulfate and the solvent removed in vacuo to give an oil (1 g).

The oil was purified by flash chromatography on silica gel using a 95: 5 mixture of toluene and triethylamine as eluent. Appropriate fractions were combined and the solvents were removed in vacuo to leave an oil (0.34 g). The oil was dissolved in ether and the solution was saturated with hydrogen chloride to give a solid which was collected by filtration, washed with ether and dried in vacuo to give 5-phenyl-1-azspiro [5.5] Undek-4-ene hydrochloride , as a white solid. Yield 0.36 g; m.p. 268-275 ° C (decomposition).

Example 25

Magnesium metal (0.75 g) was added, under nitrogen, about one-fourth of a solution of 4-bromobiphenyl (7.2 g) in ether (80 ml). A few drops of iodomethane were added and when the exothermic reaction started, the mixture was allowed to warm to reflux while stirring. The remaining 4-bromobiphenyl solution was added dropwise at reflux temperature, then the mixture was stirred at reflux temperature for 0.5 hour and the solvent was removed by distillation at atmospheric pressure. At room temperature, a solution of 1-azaspiro [5.5! Was added dropwise. undecan-5-one (2.2 g; prepared as described in Example B) in toluene (120 ml) and the mixture was stirred at 95 ° C for 18 hours. The mixture was cooled with the addition of excess saturated ammonium chloride solution (300 ml) and the product extracted into ether (3 x 300 ml + 1 x 400 ml). The extracts were combined and dried over magnesium sulfate and the solvents removed in vacuo to leave a brown semi-solid (6.74 g). This semi-solid was triturated with ethyl acetate to give a solid which was collected by filtration and dried in vacuo to give 5- (4-biphenyl) -5-hydroxy-1-azaspiro [5.5] undecane, as gray-white solid. Yield 1.3 g.

A mixture of 5- (4-biphenyl) -5-hydroxy-1-azaspiro [5.5 gendecane (1.3 g), toluene and p-toluenesulfonic acid (0.9 g) was heated for 38.5 hours while stirring. the reaction water was removed by azeotropic distillation. P-toluenesulfonic acid (0.9 g) was added and reflux was continued for 18 hours. P-toluenesulfonic acid (1.8 g) was added and reflux was continued for 72 hours. The mixture was basified by the addition of 5 M aqueous sodium hydroxide solution (500 ml) and the product extracted into ether (200 ml + 300 ml). The extracts were combined, dried over magnesium sulfate and the solvents removed in vacuo to give a light brown gum (1.15 g).

The product was dissolved in a 1: 1 mixture of ether and ethyl acetate (150 ml) and the solution cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration and dried in vacuo at room temperature for 16 hours and at 85 ° C for 8 hours to give 5- (4-biphenyl) -1azaspiro [5.5] undec-4-ene hydrochloride as a light brown solid. Yield 0.9 g; m.p. 288-292 ° C (decomposition) (rises at 280 ° C).

Example 26

A mixture of ethyl 1-aminocyclohexanecarboxylate (58 g; prepared as described in Example A), potassium carbonate (59 g) and ethyl 3bromopropionate (61.4 g) was stirred at 110-135 ° C for 32.5 hours at 120145 ° C for 3.5 hours and at 145-150 ° C for another 3 hours, then poured into a kidney (600 ml). The product was extracted into ether (2 x 400 ml) and the extracts were combined, dried over magnesium sulfate and the solvent removed in vacuo to leave a yellow oil (63.75 g). The oil was distilled to give ethyl 1- (2-ethoxycarbonyl ethylamine) cyclohexanecarboxylate as a colorless oil. Yield 26.3 g; boil. 126-135 ° C at 0.95 mbar.

Sodium (5.0 g) was dissolved in ethanol (280 ml) and the solvent removed in vacuo. The residue was mixed with ethyl 1- (2-ethoxycarbonylethylamino) cyclohexanecarboxylate (26.3 g) and the mixture heated to 120 ° C while stirring, while the ethanol formed in the reaction was removed by distillation. When ethanol release ceased, the mixture was allowed to cool slowly and water (100 ml) and hydrochloric acid (50 ml) were added. The mixture was heated at 95 ° C for 41 hours, then cooled to room temperature and basified by the addition of 5 M aqueous sodium hydroxide solution. The product was extracted into ether (3 x 400 ml) and the extracts were combined, dried over magnesium sulfate and the solvent removed in vacuo to leave 1-azaspiro 4.5 decan-4-one as a brown oil. Yield 12.8 g.

4-chlorophenylmagnesium bromide was prepared by adding 4-bromochlorobenzene solution (22 g) to the magnesium metal (3.4 g), initially at room temperature, and then, when the exothermic reaction began, at reflux temperature. g) in ether (220 ml). After the addition was complete, the mixture was stirred at reflux temperature

1.5 hours. A solution of 1-azaspiro [4.5decan-4-one (9 g) in toluene (220 ml) was added dropwise and the ether solvent was removed by distillation. After complete addition, the mixture was stirred at 100-110 ° C for 45 minutes and then allowed to stand at room temperature for 16 hours. The mixture was heated at 140 ° C for 2 hours, then cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride (500 ml). The product was extracted into ethyl acetate (2 x 300 ml; 1 x 200 ml) and the extracts were combined, dried over magnesium sulfate and the solvent removed in vacuo to leave an orange / brown semi-solid (11.0 g).

The semi-solid was triturated with ethyl acetate and the resulting solid was collected by filtration and dried in vacuo at 50 ° C to give 4 (4-chlorophenyl) -4-hydroxy-1-azaspiro [4.5decane as a white solid ( 2.4 g) containing an impurity identified as 4-hydroxy-lazaspiro [4.5decane-1,3-diene. This crude product was used in the next step without being purified.

The crude 4- (4-chlorophenyl) -4-hydroxy-1-azaspiro [4,5] decane (2.2 g) was dissolved in concentrated sulfuric acid (27 ml) and the solution was stirred at room temperature for 1 hour. The mixture was poured into ice to give a white precipitate, which was collected by filtration, dissolved in water and basified by the addition of 5 M aqueous sodium hydroxide solution. The product was extracted into ether (3 x 200 ml) and the extracts were combined, dried over magnesium sulfate and concentrated in vacuo to 100 ml. The solution was saturated with hydrogen chloride and the resulting solid was collected by filtration and dried in vacuo at 60 ° C for 7 hours to give 4- (4-chlorophenyl) -1-azaspiro [4.5] dec-3-one hydrochloride as a white solid substance. Yield 1.1 g; m.p. 225233 ° C (decomposition).

Example 27

The use of the compounds of this invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this specification, the term active compound means any compound of the invention, but in particular any compound that is the end product of one of the foregoing examples.

a) Capsules

In the capsule preparation, break up the aggregates and mix 10 parts by weight of the active compound and 240 parts by weight of lactose. The mixture is filled with solid gelatin capsules such that each capsule contains the dosage unit of the active compound.

b) Tablets

The tablets are prepared from the following ingredients.

Weighting parts

The active compound 10 Lactose 190 Corn starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, lactose and part of the starch are de-aggregated, mixed and the resulting mixture granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with magnesium stearate and starch residue. The mixture is then compressed in a tabletting machine to obtain tablets which each contain a dosage unit or part of the dosage unit of the active compound.

c) enteric coated tablets

The tablets are prepared by the method described in b) above. The tablets were enteric-coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Suppositories

In the preparation of suppositories, we incorporate 100 parts by weight of the active ingredient42 into 1300 parts by weight of the triglyceride base for suppositories, and the mixture is formulated into suppositories each containing a therapeutically effective amount of the active ingredient.

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PATENT APPLICATIONS

Claims (18)

Compounds of formula I and their pharmaceutically acceptable salts, in which m is an integer from 1 to 3; n is an integer from 2 to 6; R1 is phenyl optionally substituted by one or more substituents selected from: halo, hydroxy, alkoxy containing 1 to 3 carbon atoms, alkanoyl containing 2 or 3 carbon atoms, alkyl containing 1 to 3 carbon atoms, halogenated alkyl containing 1 to 3 carbon atoms, alkylthio containing 1 to 3 carbon atoms, alkylsulfinyl containing 1 to 3 carbon atoms, alky 1sulfones 1 containing 1 to 3 carbon atoms, cyano, nitro, amino optionally substituted by 1 or 2 alkyl groups each containing 1 to 3 carbon atoms, carbamoyl optionally substituted by 1 to 2 alkyl groups each containing 1 to 3 carbon atoms, or phenyl, or R 1 is naphthyl; R8 is H, alkyl containing 1 to 3 carbon atoms, or phenyl; R3 is H, alkyl containing 1 to 6 carbon atoms, alkenyl containing 3 to 6 carbon atoms or alkoxyalkyl, in which the alkoxy group contains 1 to 4 carbon atoms and the alkyl group 2 to 4 carbon atoms; R4 is H or hydroxy; and Rg is H or together with R ₄ represents a bond. Compounds of formula I according to claim 1, characterized in that R1 is phenyl optionally substituted by one or more substituents selected from: halo, hydroxy, halogenated alkyl containing 1 to 3 carbon atoms in which halo is fluoro , alkoxy containing 1 to 2 carbon atoms, or phenyl, or R1 is naphthyl. Compounds of formula I according to any one of the preceding claims, characterized in that R 1 is phenyl optionally substituted by one or more substituents selected from: chloro, fluoro, hydroxy, trifluoromethyl, methoxy or phenyl, or R 1 is naphthyl. Compounds of formula I according to any one of the preceding claims, characterized in that R 1 is phenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3- (trifluoromethyl) phenyl, 4-hydroxyphenyl, 4methoxyphenyl, 4-biphenylyl or 2-naphthyl. Compounds of formula I according to any one of the preceding claims, characterized in that Rg is H. Compounds of formula I according to any one of the preceding claims, characterized in that Rg is H, alkyl containing 1 to 3 carbon atoms, alkenyl containing 3 to 6 carbon atoms, or alkoxyalkyl in which the alkoxy group contains 1 up to 3 carbon atoms and the alkyl group 2 or 3 carbon atoms. Compounds of formula I according to any one of the preceding claims, characterized in that R 8 is H, methyl, ethyl, propyl, allyl or 2-methoxyethyl. Compounds of formula I according to any one of the preceding claims, characterized in that R 8 is H. Compounds of formula I according to any one of the preceding claims, characterized in that R ₄ is hydroxy and Rg is H, R ₄ and Rg are both H, or R ₄ and Rg together are a bond. Compounds of formula I according to any one of the preceding claims, characterized in that R4 and Rg together represent a bond. Compounds of formula I according to claim 1, characterized in that they are: 5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene; 5- (3-chlorophenyl) -1-azaspiro [5.5] undec-4-ene; 5- (3,4-di-chlorophenyl) -1-azaspiro [5.5] undec-4-ene; 5- (4-fluorophenyl) -1-azaspiro [5.5] undec-4-ene; 5- [3- (trifluoromethyl) phenyl] -1-azaspiro [5.5] undec-4-ene; 5- (2-naphthyl) -1-azaspiro [5.5] undec-4-ene; 5- (4-hydroxyphenyl) -1-azaspiro [5.5] undec-4-ene; 5- (4-chlorophenyl) -1-methyl-1-azaspiro [5.5] undec-4-ene; 10- (4-chlorophenes 1) -6-azaspiro [4.5] dec-9-ene; 5- (4-chlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane; 5- (4-chlorophenyl) -1-ethyl-5-hydroxy-1-azaspiro [5.5] undecane; 5- (3-chlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane; 5- (3,4-Dichlorophenyl) -5-hydroxy-1-azaspiro [5.5] undecane; 5- (4-chlorophenyl) -1-azaspiro [5.5] undecane; 5- (4-methoxy and phenyl) -1-azaspiro [5.5] undecane; 5- (4-chlorophenyl) -1-propyl-1-azaspiro [5.5] undec-4-ene; 1-allyl-5- (4-chlorophenyl) -1-azaspiro [5.5] undec-4-ene; 5- (4-chlorophenyl) -1- (2-methoxyethyl) -1-azaspiro [5.5] undec-4-ene; 5-phenyl-1-azaspiro [5.5] undec-4-ene; 5- (4-bi-phenyl) -1-azaspiro [5.5] undec-4-ene; 4- (4-chlorophenyl) -1-azaspiro [4.5] undec-3-ene; and pharmaceutically acceptable salts thereof. Pharmaceutical compositions characterized in that they contain a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier. A compound of formula I according to any one of claims 1 to 11 for use in the treatment of obesity. A compound of formula I according to any one of claims 1 to 11 for use in the treatment of emotional disorders. A compound of formula I according to any one of claims 1 to 11 for use in the treatment of depression. A compound of formula I according to any one of claims 1 to 11 for use in the treatment of anxiety. Use of a compound of formula I according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of obesity. Use of a compound of formula I according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of emotional disorders.